If I had to place money on a neurotech that will win the Nobel Prize, it’s optogenetics.

The technology uses light of different frequencies to control the brain. It’s a brilliant mind-meld of basic neurobiology and engineering that hijacks the mechanism behind how neurons naturally activate—or are silenced—in the brain.

Thanks to optogenetics, in just ten years we’ve been able to artificially incept memories in mice, decipher brain signals that lead to pain, untangle the neural code for addiction, reverse depression, restore rudimentary sight in blinded mice, and overwrite terrible memories with happy ones. Optogenetics is akin to a universal programming language for the brain.

But it’s got two serious downfalls: it requires gene therapy, and it needs brain surgery to implant optical fibers into the brain.

This week, the original mind behind optogenetics is back with an update that cuts the cord. Dr. Karl Deisseroth’s team at Stanford University, in collaboration with the University of Minnesota, unveiled an upgraded version of optogenetics that controls behavior without the need for surgery. Rather, the system shines light through the skulls of mice, and it penetrates deep into the brain. With light pulses, the team was able to change how likely a mouse was to have seizures, or reprogram its brain so it preferred social company.

To be clear: we’re far off from scientists controlling your brain with flashlights. The key to optogenetics is genetic engineering—without it, neurons (including yours) don’t naturally respond to light.

However, looking ahead, the study is a sure-footed step towards transforming a powerful research technology into a clinical therapy that could potentially help people with neurological problems, such as depression or epilepsy. We are still far from that vision—but the study suggests it’s science fiction potentially within reach.

Opto-What?

To understand optogenetics, we need to dig a little deeper into how brains work.

Essentially, neurons operate on electricity with an additional dash of chemistry. A brain cell is like a living storage container with doors—called ion channels—that separate its internal environment from the outside. When a neuron receives input and that input is sufficiently strong, the cells open their doors. This process generates an electrical current, which then gallops down a neuron’s output branch—a biological highway of sorts. At the terminal, the electrical data transforms into dozens of chemical “ships,” which float across a gap between neurons to deliver the message to its neighbors. This is how neurons in a network communicate, and how that network in turn produces memories, emotions, and behaviors.

Optogenetics hijacks this process.

Using viruses, scientists can add a gene for opsins, a special family of proteins from algae, into living neurons. Opsins are specialized “doors” that open under certain frequencies of light pulses, something mammalian brain cells can’t do. Adding opsins into mouse neurons (or ours) essentially gives them the superpower to respond to light. In classic optogenetics, scientists implant optical fibers near opsin-dotted neurons to deliver the light stimulation. Computer-programmed light pulses can then target these newly light-sensitive neurons in a particular region of the brain and control their activity like puppets on a string.

It gets cooler. Using genetic engineering, scientists can also fine-tune which populations of neurons get that extra power—for example, only those that encode a recent memory, or those involved in depression or epilepsy. This makes it possible to play with those neural circuits using light, while the rest of the brain hums along.

This selectivity is partially why optogenetics is so powerful. But it’s not all ponies and rainbows. As you can imagine, mice don’t particularly enjoy being tethered by optical fibers sprouting from their brains. Humans don’t either, hence the hiccup in adopting the tool for clinical use. Since its introduction, a main goal for next-generation optogenetics has been to cut the cord.

Goodbye Surgery

In the new study, the Deisseroth team started with a main goal: let’s ditch the need for surgical implants altogether. Immediately, this presents a tough problem. It means that bioengineered neurons, inside a brain, need to have a sensitive and powerful enough opsin “door” that responds to light—even when light pulses are diffused by the skull and brain tissue. It’s like a game of telephone where one person yells a message from ten blocks away, through multiple walls and city noise, yet you still have to be able to decipher it and pass it on.

Luckily, the team already had a candidate, one so good it’s a ChRmine (bad joke cringe). Developed last year, ChRmine stands out in its shockingly fast reaction times to light and its ability to generate a large electrical current in neurons—about a 100-fold improvement over any of its predecessors. Because it’s so sensitive, it means that even a spark of light, at its preferred wavelength, can cause it to open its “doors” and in turn control neural activity. What’s more, ChRmine rapidly shuts down after it opens, meaning that it doesn’t overstimulate neurons but rather follows their natural activation trajectory.

As a first test, the team used viruses to add ChRmine to an area deep inside the brain—the ventral tegmental area (VTA), which is critical to how we process reward and addiction, and is also implicated in depression. As of now, the only way to reach the area in a clinical setting is with an implanted electrode. With ChRmine, however, the team found that a light source, placed right outside the mice’s scalp, was able to reliably spark neural activity in the region.

Randomly activating neurons with light, while impressive, may not be all that useful. The next test is whether it’s possible to control a mouse’s behavior using light from outside the brain. Here, the team added ChRmine to dopamine neurons in a mouse, which in this case provides a feeling of pleasure. Compared to their peers, the light-enhanced mice were far more eager to press a lever to deliver light to their scalps—meaning that the light is stimulating the neurons enough for the mice to feel pleasure and work for it.

As a more complicated test, the team then used light to control a population of brain cells, called serotonergic cells, in the base of the brain, called the brainstem. These cells are known to influence social behavior—that is, how much an individual enjoys social interaction. It gets slightly disturbing: mice with ChRmine-enhanced cells, specifically in the brainstem, preferred spending time in their test chamber’s “social zone” versus their siblings who didn’t have ChRmine. In other words, without any open-brain surgery and just a few light beams, the team was able to change a socially ambivalent mouse into a friendship-craving social butterfly.

Brain Control From Afar

If you’re thinking “creepy,” you’re not alone. The study suggests that with an injection of a virus carrying the ChRmine gene—either through the eye socket or through veins—it’s potentially possible to control something as integral to a personality as sociability with nothing but light.

To stress my point: this is only possible in mice for now. Our brains are far larger, which means light scattering through the skull and penetrating sufficiently deep becomes far more complicated. And again, our brain cells don’t normally respond to light. You’d have to volunteer for what amounts to gene therapy—which comes with its own slew of problems—before this could potentially work. So keep those tin-foil hats off; scientists can’t yet change an introvert (like me) into an extrovert with lasers.

But for unraveling the inner workings of the brain, it’s an amazing leap into the future. So far, efforts at cutting the optical cord for optogenetics have come with the knee-capped ability to go deep into the brain, limiting control to only surface brain regions such as the cortex. Other methods overheat sensitive brain tissue and culminate in damage. Yet others act as 1990s DOS systems, with significant delay between a command (activate!) and the neuron’s response.

This brain-control OS, though not yet perfect, resolves those problems. Unlike Neuralink and other neural implants, the study suggests it’s possible to control the brain without surgery or implants. All you need is light.

Image Credit: othebo from Pixabay

Shelly Xuelai Fan is a neuroscientist-turned-science writer. She completed her PhD in neuroscience at the University of British Columbia, where she developed novel treatments for neurodegeneration. While studying biological brains, she became fascinated with AI and all things biotech. Following graduation, she moved to UCSF to study blood-based factors that rejuvenate aged brains. She is the ...

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